Day: July 5, 2024

Animals and humans coexist with a vast array of microorganisms known as the microbiome, forming a relationship that can range from mutually beneficial to pathogenic. To safeguard against harmful pathogens and maintain the presence of beneficial microorganisms, animals have evolved various defenses.One is small antimicrobial peptides (AMPs), small peptides that combat invading microbes. AMPs are crucial immune effectors in plants and animals, fighting against potential infections while also influencing the composition of the host’s microbiome. While previous studies have shown that AMPs evolve rapidly, little was known about the driving forces behind this evolution. For example, different animals have different “repertoires” of AMP genes, while lacking others found elsewhere. Understanding the evolutionary “logic” behind this is important not just as an ecological study, but also for the development of strategies to prevent infections by targeting specific microbial threats. Now, a study led by three scientists at EPFL (École Polytechnique Fédérale de Lausanne) in Switzerland has uncovered the selective pressures driving the evolution of AMPs and how they control bacteria in the host’s microbiome. The work was carried out by Bruno Lemaitre’s group at EPFL’s School of Life Sciences, led by Mark Hanson (now at the University of Exeter) and Lena Grollmus. It is published in Science. The researchers focused on diptericin (Dpt), a small antimicrobial peptide that mainly defends flies against Gram-negative bacteria, disrupting their bacterial membrane. Looking at the fruit fly, Drosophila, the team examined how diptericins function and evolve in response to their microbial environment. The team discovered that different types of diptericins, known as DptA and DptB, play specific roles in the fruit fly’s defense against different bacteria. By screening Drosophila mutants lacking specific AMP gene families, the researchers found that DptA is effective against Providencia rettgeri, a natural pathogen of Drosophila. Meanwhile, DptB helped the host resist infection by multiple species of Acetobacter, some of which reside in the fruit fly’s gut and help its physiology and development. In contrast, DptA played no significant role against Acetobacter and DptB played no significant role against Providencia. Evolutionary history Analyzing the evolutionary history of the diptericin genes, the scientists found two instances of convergent evolution that lead to DptB-like genes in fruit flies that feed on fruit, an environment associated with high levels of Acetobacter. This suggests that DptB evolved to control Acetobacter in the ancestral fruit-feeding Drosophila. The study also found that fruit flies with different ecological niches, such as mushroom-feeding or being plant-parasites, had either lost the DptB gene or both DptA and DptB genes, corresponding to an absence of Acetobacter or both Providencia and Acetobacter, respectively. Variations in DptA and DptB sequences were found to predict the host’s resistance to infection by these bacteria throughout the Drosophila genus. This highlights the evolutionary adaptation of the fly’s immune repertoire to combat specific microbes prevalent in its surroundings. To validate their findings, the researchers infected various Drosophila species with different variants of DptA and DptB genes. The researchers said the results were striking: the resistance of the host to infection by P. rettgeri and Acetobacter was readily predicted just by the presence and polymorphism of the DptA or DptB genes, even across fly species separated by almost 50 million years of evolution. The work sheds light on the dynamics that shape the host’s immune system and how the host’s defenses adapt to combat specific pathogens while fostering beneficial microorganisms. The findings propose a new model of AMP-microbiome evolution, incorporating gene duplication, sequence convergence, and gene loss, all guided by the host’s ecology and microbiome. This model explains why different species possess specific repertoires of AMPs, offering insights into how host immune systems rapidly adapt to the suite of microbes associated with a new ecological niche. “The way our bodies fight infections is very complex,” Hanson said. “But this sort of research helps us to view our immune system in a new light. It helps us ask: ‘why is our immune system made the way it is?’ That can help us learn how to fight infections, including ones that resist antibiotics.” Looking to expand your network? Build relationships with world-leading academic teams at 250+ institutes. ADVERTISEMENT

In a recent study published in Nature, researchers describe the findings of the COVID-19 Citizen Science Study, a large-scale study directly examining human leukocyte antigen (HLA) variation(s) in a prospective cohort comprising individuals with mild coronavirus disease 2019 (COVID-19). They invited 29,947 volunteer bone marrow donors with high-resolution HLA genotyping data to develop this prospective cohort and two additional independent cohorts. Study: A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Image Credit: sciencepics/Shutterstock.com Background Numerous studies intending to understand the genetic basis of differential outcomes in COVID-19 have examined genetic associations with severe disease course, primarily in hospitalized cohorts, e.g., the multicentre Host Genetics Initiative. However, few studies have examined genetics in non-hospitalized, prospective, community-based cohorts. Studies directly examining HLA associations with infection had relatively small cohorts and fetched mixed and inconclusive results. Hundreds of genes govern human immune responses to diseases, of which HLA variants have the most robust associations with viral infections. It makes them relevant molecular targets for COVID-19 vaccine development. Individuals expressing HLA-B*46:01 might be more vulnerable to COVID-19. Conversely, HLA-B*15:03 protects against COVID-19 by presenting highly conserved SARS-CoV-2 peptides to T cells. More in-depth insights into the impact of HLA variation(s) in infectious diseases could inform vaccine development and potential immunotherapies for COVID-19. About the study The present study had a smartphone-based study design which helped the researchers track COVID-19 symptoms and outcomes, including positive reverse transcription-polymerase chain reaction (RT-PCR) test results of nearly 30,000 individuals previously HLA genotyped for five loci, HLA-A, -B, -C, -DRB1 and -DQB1. Related Stories Notably, they included positive test result data till 30 April 2021 from people who self-identified as belonging to the ‘white’ ethnicity. They retrieved their data from a pre-existing database for medical research named the National Marrow Donor Program (NMDP). Further, they contextualized the study results by examining T cell reactivity, T cell receptor (TCR) repertoire, affinity, and structural implications for the observed HLA associations. Furthermore, the researchers examined the crystal structures of the HLA-B*15:01 molecule in a complex with peptides from other seasonal coronaviruses (CoVs), e.g., HKU1-CoV and OC43-CoV, at concentrations of five μM and ten μM. Results The main study finding was that the HLA-B*15:01 allele was markedly associated with asymptomatic infection in participants reporting a SARS-CoV-2-positive test result. Nearly 10% of individuals with European ancestry carry this common allele and remain asymptomatic post-SARS-CoV-2 infection than those who do not. Another important effect of HLA-B*15:01 homozygosity was that it increased the likelihood of remaining asymptomatic during SARS-CoV-2 infection by >eight times. Asymptomatic patients in two independent cohorts of the study also had highly similar frequency distributions of HLA-B*15:01. Furthermore, the study results showed that the HLA-DRB1*04:01 allele augmented the HLA-B*15:01 effect when paired, like in the United States (US)-origin people who self-identified as white. Upon analyzing immunodominant epitopes in T cells in human peripheral blood mononuclear cells or PBMCs from pre-pandemic healthy donors, the authors observed that the cells from donors carrying HLA-B*15:01 allele unexposed to SARS-CoV-2 were reactive to the SARS-CoV-2 spike (S) peptide NQK-Q8, and most cells displayed a memory phenotype. Thus, this amino acid sequence identity between seasonal CoVs and SARS-CoV-2 S peptides explains the T cell cross-reactivity. The presence of high-affinity, cross-reactive memory T cells in unexposed donors further corroborated the robust association between the allele HLA-B*15:01 and asymptomatic COVID-19. Other recent studies have also shown that SARS-CoV-2-specific memory T cells are enriched at the site of infection and help rapidly clear the overt onset of symptoms by secreting more interferon-gamma (IFN-Ύ). S peptides from SARS-CoV-2 and other CoVs, namely NQK-Q8 and NQK-A8, showed comparably stabilized the HLA-B*15:01 molecule. Also, HLA-B*15:01 presented these peptides in similar structural conformation, which gives a molecular basis to pre-existing immunity and T-cell cross-reactivity. More importantly, despite limited data on HLA-B*15:01 epitopes found in SARS-CoV-2 patients, this study’s results found NQK-Q8 as the prime candidate peptide governing HLA-B*15:01-mediated T cell cross-immunity with seasonal CoVs. Conclusions The study results strongly support the role of the HLA-B*15:01 allele in mediating asymptomatic COVID-19 through pre-existing T-cell immunity due to previous exposure to other CoVs. The understanding that HLA class I alleles play a crucial role in early infection and the mechanisms underlying early viral clearance leading to asymptomatic SARS-CoV-2 infection have important implications. It becomes the framework for future studies refining vaccine development and therapies for early disease. Journal reference:

Even with the extreme scarcity of available data, there is sufficient information from the limited reporting on levels of SARS-CoV-2 in wastewater to conclude a summer surge in COVID infections is well under way in the United States. It began even before mid-May, when President Joe Biden terminated the national COVID emergency response, effectively turning out all the lights on any direct measurement of the state of the pandemic. As shown by the CDC graph below, in April 2023 levels of SARS-CoV-2 in wastewater began to rise steadily, an indirect indicator of community-level spread. Over the month of June, there was a more than 60 percent rise in wastewater levels of the virus, with more than 1,300 sites participating in providing the public health agency with data. It is worrisome however that in the last two weeks of July there has been a precipitous drop in the number of sites reporting these figures (a 22 percent decline) with a corresponding blunting of the SARS-CoV-2 levels reported. Although the CDC explained that this is a normal lag and data would be added retroactively, given the agency’s previous lack of transparency, such assurances cannot be taken as read. Percent of sites in each percent change category over time, United States. [Photo: Centers for Disease Control and Prevention] For instance, a similar phenomenon occurred in late December 2022 when there was a precipitous drop in SARS-CoV-2 wastewater levels with a corresponding drop in the number of sites reporting, amid an ongoing winter surge of infections. The CDC blamed the Christmas holiday season for the aberration, but this was completely irresponsible. Precisely when a massive surge in cases was under way, the necessary data to “inform the public” was conveniently unavailable. There was a huge drop in the virus level, but that is likely due to the sites that contribute most, in metropolitan areas, going dark. It would not be surprising to see this effective blackout repeated, so that in the next few weeks we might hear the CDC claim that the summer break led to a decline in participating facilities, hiding the advance of another surge. If one were to extrapolate the end of June projections into July, they suggest not only has the peak in cases not been reached, but that it will match or exceed the level of COVID in previous winter and summer peaks. Data from Biobot Analytics, which is considered more reliable than the limited CDC reporting, confirms the ongoing surge in wastewater coronavirus right up to the present. Biobot explained that they use statistical techniques that adjust for dilution and population size and, as wastewater-based epidemiology advances, they will adjust to account for the technical factors and introduce “the concept of effective concentration as a transparent and future-proof approach” that will ensure the data reliably reflects trends in the population-wide COVID-19 burden.” As Biobot noted, the current epicenters for the summer 2023 COVID surge are in the Northeast and South, where in conjunction with the rise in wastewater virus levels, the heat wave and the air pollution from the Canadian forest fires have driven people indoors. In California, Los Angeles has recently reported a rise in COVID cases although their figures, as they note, represent only a fraction of actual COVID cases, suggesting the summer COVID wave is just beginning in the second largest US city. The reliance by the CDC on wastewater surveillance underscores the reality that such indicators lack any real-time value, are prone to manipulation and provide little clinical guidance to direct local public health authorities and health systems. The agency uses wastewater tracking to inure the population against the threat posed by COVID or any other pathogen, while maintaining the farce that the national public health edifice is functioning to protect the population, although hardly anyone believes that any more. As data scientist and modeler JWeiland noted on his Twitter social media account, the current wastewater SARS-CoV-2 levels correspond to an estimated daily infection rate of more than 310,000 or a ratio of one in every 1,060 people becoming infected every day and at least one percent of the population currently infected. Irrespective of the current low fatality rate which is still higher than the flu and could skyrocket should viral evolution produce a more deadly variant, as it has in the past, one in 10 people infected with Omicron sub-variants develop Long COVID, regardless of disease severity or age. US COVID Projections July 18, 2023. [Photo by J. Weiland] As Dr. Marc Sala of Northwestern University Medicine recently said, “You will have many patients come to us still in good numbers to fill up our clinic with maybe the third, fourth, fifth infection and now having finally developed post-COVID syndrome … with symptoms that are enough to be disabling to their lives as previously known.” Although these patients are filling up hospitals and ICUs as in the past, the long-term implications are even worse. Long COVID is already the third leading cause of neurological disorders. Mehring Books COVID, Capitalism, and Class War: A Social and Political Chronology of the Pandemic A compilation of the World Socialist Web Site‘s coverage of this global crisis, available in epub and print formats. Buy your copy today In children, the lingering effects after a COVID infection can include various neurocognitive complaints like loss of smell, fatigue, and brain fog. These lead to the inability to think or remember clearly. More serious signs include atrophy of the brain’s grey matter, which can be associated with cognitive dysfunction and symptoms like anxiety and depression. These findings have been repeated internationally and will have long-lasting consequences and harken back to the lie perpetrated during the first years of the pandemic that children are immune to the ravages of the disease. Nonetheless, the current surge has finally provided the first clinical glimpse of its impact on the national arena despite the very limited surveillance capacity. Emergency room visits climbed 7.1 percent compared to the previous week. The test positivity rate,